Nicotine, mainly found in tobacco and other nightshade family of plants is essentially a parasympathomimitic alkaloid and is a stimulant drug. Nicotine is directly related to smoking of tobacco, as it results in nicotine dependence and is habit forming. Smoking is not only habit forming, it may also lead to the diseases of lungs including malignant growth and harmful effects of smoking are well recognized globally. Inspite of knowing these serious effects, unfortunately habitual smokers cannot overcome their dependency and is still habit forming. In early 1990s nicotine replacement therapy was widely promoted by World Health Organization to overcome the dependency on cigarette and to give-up smoking. In this direction, products containing minimal quantities of nicotine were developed and promoted as substitutes for traditional smoking agents like cigarettes etc. Nicotine was also found to be a promising and effective drug, which is therapeutically used for treating Alzheimer's disease, schizophrenia, Parkinson's syndrome, Tourette's syndrome, attention deficit disorder, depression etc.
The natural nicotine is levogyric and is chemically denoted as (S)-3-(1-methyl-2-pyrrolidinyl)pyridine. Tobacco is the prime source for nicotine and the nicotine isolated from tobacco contains other related alkaloids and degradation products as impurities. Therefore the impurities present in natural nicotine are not fixed always and may vary depending on the geographical origin and climatic conditions etc. With these features, the natural nicotine always contains closely related impurities and which are very difficult to remove. The pharmacopoeias also recognize these variations and have different limits for the impurities listed.
The racemic nicotine was also found to have similar pharmacological effect as that of natural nicotine. It is only slightly less potential, but has much lower toxicity than the natural nicotine. It is very much straightforward that, the nicotine obtained from synthetic process is expected to be free from the impurities that are present in the natural nicotine. By synthetic method, one can prepare optically pure as well as racemic versions of nicotine from lab scale to industrial production. The racemic synthesis is a simpler process compared to the enantioselective synthesis, which is difficult to practice at the industrial scale. Therefore, synthesis of (R,S)-nicotine followed by resolution is the best process to explore. The resolution of racemic nicotine is well documented in the literature using d-tartaric acid (J. Med. Chem. 1979, 22, 174-177) or enzymatic resolution (Applied and Environmental Microbiology, 1980, 39, 1067-1069).
Till date, several synthetic processes for the nicotine are reported in the literature, some of these are for the synthesis of (S)-nicotine (J. Org. Chem. 1982, 41, 1069-1073; Tetrahedron Letters, 1999, 40, 7847-7650; Synlett 2009, 9, 1413-1416) and some others are for racemic nicotine. A racemic synthesis of nicotine starting from pyrrolidine (Journal of Organic Chemistry, 1990, 55, 1736-44) could be carried out in a four step reaction sequence. The use of tert-butyl lithium and low reaction temperatures are the limitations for this process to be effective at industrial production. Another synthesis of nicotine starting from nicotinic acid (Perkin Transactions I, 2002, 143-154) also involves a four step reaction sequence and in this process the use of Grignard reagent limits its usage at industrial scale.
The other reported methods for the synthesis of racemic nicotine are (a) Synlett, 2009, 2497-2499; (b) Journal of Heterocyclic Chemistry, 2009, 46, 1252-1258; (c) U.S. Pat. No. 8,389,733 (d) U.S. Pat. No. 8,884,021. Though, several of these methods are practical at laboratory level, only few of them are useful at industrial production. Most of these reported methods are difficult to be practiced at the industrial production due to one or more of the following factors: (a) expensive reagents and/or raw materials (b) uneven temperature and/or reaction times (c) multi-step process (d) operationally difficult reaction conditions/parameters.